Phase I/II study of ipilimumab plus nivolumab combined with sacituzumab govitecan in patients with metastatic cisplatin-ineligible urothelial carcinoma.
Authors: Rohit K. Jain, Yuanquan Yang, Juskaran Chadha, Monica Sheila Chatwal, Julie Ann Kish, Sarah Raymond, Jennifer Rembisz, Ghazal Jameel, Arfa Mustasam, Trey Poehlman, Wenyi Fan, Youngchul Kim, Jasreman Dhillon, Carlos A. Alemany, Amir Mortazavi, Jingsong Zhang, Guru P. Sonpavde
Journal: Journal of Clinical Oncology (2023)

521 Background: Sacituzumab govitecan (SG) demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months (Mo) in metastatic urothelial carcinoma (mUC) patients (pts) progressing after platinum-based chemotherapy and PD1/L1 inhibitor, which led to accelerated US FDA approval in this setting. The combination of SG and pembrolizumab is safe and active following platinum-based chemotherapy. Nivolumab (NIVO) 1mg/kg plus Ipilimumab (IPI) 3mg/kg has shown promising activity in post-platinum mUC pts. Given the potential synergism between immunogenic cell death induced by SG and IPI-NIVO, we hypothesized that the combination of SG and IPI-NIVO would be safe and active as a frontline treatment for cisplatin ineligible mUC. Methods: 3+ 3 design was used for the phase I dose escalation of SG at 8 mg/kg and 10 mg/kg dose levels. IPI and NIVO were given at 3mg/kg and1mg/kg (I3+N1) intravenously (IV) every 3 weeks x 4 cycles followed by NIVO 360 mg IV day 1 every 3 weeks. SG was given IV at days 1,8 every 3 weeks The primary endpoint was safety and recommended phase 2 dose (RP2D) based on dose limiting toxicity (DLTs) observed in cycle 1; key secondary endpoints include ORR, DOR, PFS and OS. Key inclusion criteria were ECOG-PS 0-1, cisplatin-ineligibility, treatment naïve, no prior PD1/L1 inhibitor except &gt;3 months earlier for non-metastatic disease. Results: The study has completed the phase I dose escalation after enrolling a total of 9 patients (8 men, 1-woman, median age: 74 years). 6 patients were enrolled at SG 8 mg/kg with 1 DLT, and 3 patients at 10 mg/kg with 2 DLTs. DLTs included grade 3 skin rash (n=2) and grade 3 pneumonitis (n=1). The RP2D of SG was determined to be 8 mg/kg with I3+N1. The most common treatment related adverse events (TRAE) included anemia (66.6%) neutropenia (66.6%), pruritus (66.6%), fatigue (66.6%), diarrhea (66.6%) and lymphopenia (55.5%). 2 patients developed grade 2 infusion reactions to SG. Other grade ≥ 3 TRAE included neutropenia (55.5%), anemia (33.3%), arthralgia (11.1%), and elevated amylase/lipase (11.1%). Both grade 2 pneumonitis and myositis were seen in 1 patient. Of the 9 pts, 6 pts (4 pts at SG dose of 8mg/kg and 2 pts at 10 mg/kg) were considered evaluable for response of whom 4 responded (ORR 66.6%) with 1 complete response and 3 partial responses. Median DOR was 9.2 Mo (range 4.6-12.0); mPFS was 8.8 Mo (95% CI 3.8-NR) and mOS was not reached. Conclusions: The RP2D of SG was identified as 8mg/kg in combination with Ipilimumab 3 mg/kg+ Nivolumab 1 mg/kg as first-line therapy for cisplatin-ineligible mUC. Early signals of promising activity were observed in a small cohort of evaluable pts. The Phase 2 trial is ongoing coupled with exploratory biomarker analyses. Clinical trial information: NCT04863885 .